TRIM6 promotes colorectal cancer cells proliferation and response to thiostrepton by TIS21/FoxM1

Abstract

Background: Tripartite motif-containing proteins (TRIM) play a crucial role in carcinogenesis. Little attention has been focused on the possible functions of TRIM6 on carcinogenesis. Methods: The expression levels of TRIM6 were assessed in colorectal cancer (CRC) samples. TRIM6 expression was knocked down in CRC cell lines, and subjected to Cell counting kit-8 (CCK-8), bromodeoxyuridine (BrdU) incorporation and cell cycle assays. Immunoprecipitation and proteomics analysis was performed to identify potential associated proteins of TRIM6. Results: TRIM6 expression was up-regulated in CRC samples and TRIM6 expression may be an independent prognostic marker for CRC. Knocking down TRIM6 expression suppressed CRC cell proliferation, induced cell cycle arrested at G2/M phase and increased sensitivity to 5-fluorouracil and oxaliplatin. TIS21, an anti-proliferative protein involved in the regulation of G2/M arrest, was identified as an interaction partner of TRIM6. Moreover, CRC cells with TRIM6 overexpression showed decreased TIS21 protein stability. TIS21 ubiquitination was increased in CRC cells overexpressing TRIM6, but not in those overexpressing TRIM6 E3 catalytic mutant (C15A). Further, Lys5 was essential for TRIM6 mediated TIS21 ubiquitination. TIS21 overexpression reversed the induced effects of TRIM6 overexpression on CRC cell proliferation, and the levels of forkhead box M1 (FoxM1), phosphorylated FoxM1, Cyclin B1 and c-Myc. Thiostrepton, a specific inhibitor for FoxM1, was less effective in anti-proliferative activity against CRC cells with lower level of TRIM6 in vitro and in vivo. Conclusions: Our study suggests that TRIM6 promotes the progression of CRC via TIS21/FoxM1.

Tripartite motif-containing protein 6 facilitates growth and migration of breast cancer through degradation of STUB1

“…TRIM6 functioned as an E3-ubiquitin ligase to destabilize TIS21 during colorectal cancer progression. 10-13 STUB1 was verified as binding target of TRIM6 in this study through Co-IP analysis, and TRIM6 contributed to ubiquitination-mediated degradation of STUB1 in breast cancer cells. STUB1 was also verified as E3 ligase to participate in protein homeostasis involved in neurodegenerative diseases.…”

“… 11 TRIM44 enhanced NF-κB signaling to promote breast cancer progression, 12 and TRIM59 stabilized programmed cell death protein 10 to promote the motility of breast cancer cell. 13 Considering that TRIM6 contributed to embryonic stem cell pluripotency, 9 and promoted cell proliferation of colorectal cancer, 10 the regulatory role of TRIM6 in breast cancer progression was then investigated in this study.…”

“… 9 Recently, TRIM6 was reported to be upregulated in colorectal cancer cells, and promoted ubiquitination of anti-proliferative gene, TIS21, to facilitate the tumor progression. 10 However, the role and mechanism of TRIM6 in breast cancer remain unclear.…”

Tripartite Motif Protein 6 Promotes Colorectal Cancer Cell Migration and Metastasis via SOCS2-STAT3 Signaling

“…TRIM6 protein has been reported to promote cell cycle progression and CRC cell proliferation ( 16 ). In the in vitro and in vivo functional assays, we observed that TRIM6 promotes CRC migration.…”

“…Regarding its mechanism, TRIM6 functions as a ubiquitin ligase for c-Myc, allowing it to maintain c-Myc at an appropriate level ( 20 ). Recently published data indicate that TRIM6 promotes CRC cell proliferation ( 16 ). This finding indicates the potential function of TRIM6 in carcinogenesis and cancer metastasis.…”